Abstract: SA-OR06
MARCKS Upregulation in Macrophage Reprogramming as a Therapeutic Target in Kidney Injury and Fibrosis
Session Information
- AKI: An Inflamed State of the Union
October 26, 2024 | Location: Room 5, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Hsu, Ssu-Wei, University of California Davis, Davis, California, United States
- Chang, So-Yi, University of California Davis, Davis, California, United States
- Bhatia, Purva, University of California Davis, Davis, California, United States
- Kao, Vincent, Davis Senior High School, Davis, California, United States
- Chang, Wen-Hsien, University of California Davis, Davis, California, United States
- Chin, Andrew I., University of California Davis, Davis, California, United States
- Chen, Ching-Hsien, University of California Davis, Davis, California, United States
Background
Acute kidney injury (AKI) is characterized by sudden, reversible kidney dysfunction, with incomplete recovery potentially leading to chronic kidney injury. Macrophage infiltration and polarization are crucial in AKI recovery, yet their roles in injury development and progression remain unclear. This study aimed to identify novel therapeutic targets within pathogenic macrophages during kidney injury and resolution.
Methods
We analyzed macrophage transcriptomes to pinpoint regulators of AKI, confirming upregulation of MARCKS in macrophages within injured kidneys. To investigate the contributions of MARCKS to macrophage-mediated inflammation and fibrosis, we conducted in vitro, ex vivo, and in vivo studies using primary macrophages, precision-cut kidney slices (PCKS), and cisplatin-exposed mice with macrophage-specific MARCKS deletion.
Results
Mice with macrophage-specific Marcks deletion exhibited improved kidney function and increased survival in a severe AKI model. Furthermore, macrophage Marcks deletion conferred protection against renal fibrosis in mice with cisplatin-induced chronic kidney disease (CKD). Notably, we observed reduced macrophage infiltration and activation within the injured kidneys in both mouse models. Bone marrow–derived monocytes (BMDMs) from Marcks-knockout mice showed downregulated MARCKS phosphorylation, podosome formation, and cell motility. Co-culturing these BMDMs with injured kidney slices led to diminished chemotactic responses to macrophage chemoattractants, decreased activation of PI3K/AKT pathways, and increased apoptosis markers. PCKS derived from macrophage-specific MARCKS-knockout mice displayed fewer fibrotic lesions, less collagen deposition, and reduced pro-fibrotic macrophage presence following exposure to fibrosis inducers. Pharmacological inhibition of MARCKS activity in macrophages not only downregulated pathogenic macrophages but also reduced serum creatinine and blood urea nitrogen levels in both cisplatin-induced AKI and AKI-to-CKD models.
Conclusion
Our findings highlight the critical role of MARCKS and its phosphorylation in driving kidney fibrosis by reprogramming macrophages and modulating their pathogenic activities. This suggests that targeting MARCKS could be an effective therapeutic strategy for managing cisplatin-induced kidney diseases.
Funding
- Other NIH Support